NAD+ in Aging: Role of Nicotinamide Riboside and Nicotinamide Mononucleotide
dr. Anna Patrick here today I’m going to discuss a molecule that in recent years has become very relevant to the field of aging specifically I’m referring to nad and it’s related precursor molecules nicotinamide right aside and nicotinamide mononucleotide often referred to as nad boosters which can both be found as consumer available supplements just in case you’ve never heard of nad it’s probably one of the most important molecules on the planet so important fact that without it life would cease to exist the NAD boosters nicotinamide right aside and nicotinamide mononucleotide at very high doses in animal studies have been shown to improve the way multiple tissues and cell types age including the heart and skeletal muscle the brain and stem cells a couple of clinical studies have shown that nicotinamide right aside can increase nad levels in white blood cells which is pretty darn cool however there are still many open questions that need to be addressed and I will touch on some of those concerns in this video but the possibility that intracellular nad levels can be increased with the supplement or several types of supplements is very interesting if not downright exciting for one simple reason nad levels decrease with age and a decrease in nad levels across multiple types of tissues is associated with many and I mean many hallmarks of aging these hallmarks of aging include loss of Proteus stasis mitochondrial dysfunction glucose intolerance insulin insensitivity cellular senescence altered epigenetics and more that is partly because nad promotes DNA repair capacity and its decline is associated with an increase in DNA damaging reactive oxygen species another reason is because nad is required for energy production in every tissue for example it’s required to produce energy in the brain in immune cells and muscle tissue when nad levels decline as they do with age that means those tissues don’t function properly like they did during youth when energy levels were maintained ne D is also required to activate a very important family of time’s involved in longevity called sirtuins the complete answer as to why nad levels decrease with age is still an open question but there are a few things that we do know chronic inflammation and immune activation to processes that consume nad tend to go up with age and with them our need for DNA repair placing an immense demand on the nad pool meanwhile our ability to produce and recycle nad also decreases with age in this video we’re going to cover a lot of ground but I would first like to start with an overview of nad nad has a very important role in energy metabolism nad can be synthesized in the body from a variety of dietary sources including the amino acid tryptophan which is in tons of healthy foods like salmon spinach and nuts and the three forms of niacin which is vitamin b3 also found in foods like lean meats legumes veggies these three forms of vitamin b3 include nicotinamide also called niacin amide nicotinic acid and nicotinamide right beside they are commonly referred to as niacin equivalents but dietary sources of nad are not the major source of nad the major source of nad is through a recycling mechanism that we will discuss later the reason for that is because our organs require such large quantities of nad that it would be impossible to consume enough from our diet so why do we require such large quantities of nad first and foremost nad plays a critical role in energy metabolism critical meaning without it you can’t make energy nad participates in back and forth processes of reduction and oxidation often referred to as redox reactions these alternating conversions of nad xok citize form which is nad to its reduced form NADH are crucial for the metabolism of glucose and fatty acids and the formation of ATP since both the oxidized and reduced forms of nad are essential for these linked sets of reactions cells need to maintain massive concentrations of both nad and NADH basically without these molecules not only would we cease to exist but life on our planet would cease to exist nad is also a cofactor for many different important and in this context a cofactor means something that is required for an enzyme to work it has to bind to the enzyme and this activates the enzyme so it can perform its function so let’s talk about a few of these enzymes several of these nad required enzymes are inside the mitochondria and this is another way nad participates in the generation of energy aside from itself being a type of energetic currency it also acts as a cofactor for enzymes involved in the production of energy from glucose outside of the mitochondria this is referred to as glycolysis many types of cells use like glycolysis as their primary source of energy for example red blood cells do not have any mitochondria so a hundred percent of the energy they require to perform their function of delivering oxygen and other goodies to other tissues in the body comes from glycolysis nad plays a very important role in mitigating DNA damage you need nad to repair damage to DNA that is because nad is a cofactor for one of the most important enzymes involved in repairing DNA damage called PARP 1 the activation of PARP 1 requires an enormous amount of nad for example excessive DNA damage in subsequent park1 activation have been shown to decrease nad levels to 20 to 30% of its normal levels the ability to repair DNA damage is important for longevity lymphoblastoid cell lines established from blood samples of humans who were centenarians 100 years or older have significantly higher PARP one activity than cell lines established from younger individuals that are 70 years old PARP one activity has also been correlated with maximum lifespan in mammals the higher the PARP one activity the longer the lifespan for example the activity of PARP 1 was measured across multiple mammalian species and the difference in par point activity between the longest lived mammals tested which were humans and the shortest lived mammals tested which were rats was fivefold so not too much of a surprise but genomic stability which relies on nad in general and PARP one specifically may be very important for longevity nad is required to activate signaling proteins known as sirtuins which are highly conserved enzymes that play roles in health span and longevity in multiple organisms sirtuins are linked to the regulation of a variety metabolic processes like the response to stress and the modulation of lifespan the way they do this is through epigenetic regulation sirtuins utilize nad to remove specific chemical structures called acetyl groups a process called deacetylation from cellular proteins to control the activation of genes involved in energy metabolism at AA fuji circadian rhythm DNA repair cell survival and more when cellular energy levels are low such as during exercising fasting or Cal work restriction nad levels rise which also means the ratio of nad to its reduced form NADH increases and this serves as a sensor to switch on soar to an expression in subsequent activity resveratrol and naturally occurring compound found in red grapes and other plants is a potent sirtuin activating compound and it’s beneficial effects on healthspan some of which is now showing up in human research are thought to result from sirtuin activation alright so that is nad in a nutshell it’s important stuff unfortunately nad becomes depleted across various tissues including the brain as we age the brain skeletal muscle the heart these are all tissues with a very high metabolic demand and thus require a lot of nad so what happens when you can’t meet that metabolic demand things start to generate and fall apart they don’t work as well as I mentioned before nad depletion has been associated with the hallmarks of aging such as decrease etaf eg increased DNA damage increased mitochondrial dysfunction and dysregulated metabolism depletion of nad may predispose organisms to the development of a variety of age-related diseases including neurodegenerative disease such as Alzheimer’s disease and Parkinson’s disease cardiovascular disease and muscle atrophy it may also increase the susceptibility to infections since the immune system requires tons of nad in contrast nad levels increase under conditions that many of us already think of as generally healthspan promoting such as exercise and also fasting or in the case of lab rats full-blown lifelong caloric restriction furthermore nad restoration through a variety of different methods has been shown to increase lifespan in lower-level organisms such as yeast and worms as well as in rodents taken together these findings suggest that nad plays a critical role in aging specifically the reduction of nad levels commonly observed in aging is thought to be a combination of decreased synthesis and recycling as well as increased consumption and degradation increased DNA damage and inflammation as seen in aging may decrease nad and potentiate aging so the question that’s been on everyone’s mind is can I erase nad levels in my body and if so will that give me superpowers or at the very least help me to live healthier and free of disease longer the answer isn’t just supplements though that’s a possibility and one some labs are very excited about in pursuing in fact nad levels are heavily influenced by lifestyle and particularly things that cause energy stress like fasting caloric restriction and exercise which all raise nad remember nad can be made from things in the diet like tryptophan or niacin equivalent but these nights and equivalents are not the major source of nad the reason for that is because the body’s demand for nad exceeds its capacity to produce it from these forms of vitamin b3 so the body recycles nicotinamide using a recycling pathway called the nad salvage pathway this is the predominant source of nad let me explain how we get energy from this recycling pathway the consumption of nad from enzymes that use it generates nicotinamide as a by-product nicotinamide is converted into nicotinamide mononucleotide and subsequently into nad there are two important things to know about the NAD salvage pathway first nicotinamide has been shown to inhibit the activity of sirtuins which is not necessarily a good thing second the enzyme that converts nicotinamide into nicotinamide mononucleotide is subject to feedback inhibition by nad levels that means at a certain concentration of nad nicotinamide will no longer be converted into nicotinamide mononucleotide and subsequently nad rather it will remain nicotinamide which is unfortunate because as I just mentioned some studies have shown nicotinamide inhibits sirtuin activation remember sirtuins are involved in longevity that means you want them to be activated the other source of nad is from nicotinamide right beside which is can convert it into nicotinamide mononucleotide and subsequently nad both nicotinamide right aside and nicotinamide mononucleotide are found in low concentrations in many foods but they are also found in supplements and are referred to as nad boosters so let’s talk nad boosters these two nad precursors nicotinamide right beside and nicotinamide mononucleotide are referred to as nad boosters because in supplement form they have been shown to be well tolerated at high doses and to effectively raise nad levels and to ameliorate age associated diseases in rodents the most extensively studied nad booster is nicotinamide right beside several animal studies have shown that when nicotinamide Ryba site is orally administered at high doses it can counteract an obesogenic diet by improving insulin sensitivity it can improve endurance and strength another animal studies showed at high dose nicotinamide right aside could reverse mitochondrial damage it could increase mitochondrial biogenesis and reverse muscular atrophy and animals that had a severe muscle wasting disease nicotinamide ribose head has also been shown to have positive effects on the brain and animals it increased neurogenesis its decreased cognitive deterioration and amyloid beta production it’s also been shown to increase synaptic plasticity in mice nicotinamide mononucleotide has not been studied as extensively as nicotine my try beside but there have been several animal studies that have also shown nicotinamide mono nucleotide can have health benefits for example injection with high dose nicotinamide mononucleotide has been shown to counter an obesogenic diet and improve several markers of metabolic health high-dose injection of nicotinamide Edmondo nucleotide has been shown to improve heart function in animals with heart problems and to improve cognition and memory in animals with neurodegenerative disease a long-term study found that dietary administration of nicotinamide mononucleotide mitigated the a associated physiological decline in mice that have an accelerated aging phenotype specifically starting at five months of age mice were fed either a hundred or three hundred milligrams per kilogram body weight nicotinamide mononucleotide for twelve months these animals had improved skeletal muscle function mitochondrial function increased energy expenditure increased bone density and also decreased insulin resistance these benefits occurred in a dose-dependent manner so the higher the dose of nicotinamide modern nucleotide the greater the benefit while this all sounds great there is another important point that I want to mention while many animal studies have found that nicotinamide rye beside and nicotinamide mononucleotide can ameliorate age-related disease by increasing nad levels in different tissues there is always one disease context that throws a curveball cancer in a recent study nicotinamide mononucleotide was shown to accelerate cancer growth in mice with a type of pancreatic cancer where pro-inflammatory senescence cells drive tumor growth when mice were injected with 500 milligrams per kilogram body weight of nicotinamide mononucleotide for 13 days they exhibited significant increases in precancerous and cancerous lesions in the pancreas so let’s talk about this a little more because nicotinamide mono nucleotides effect on accelerating tumor growth was dependent on senescence cells which can disrupt normal tissue functions and ironically also drive the progression of cancer over time as well this is in spite of the fact that senescence is a program that usually prevents cancer more immediately in the short term the reason this happens is that when cells become senescent they can secrete molecules that tend to have the following qualities they are pro-inflammatory they’re involved in immune activation and evading the immune system they’re involved in growth signaling and also involved in angiogenesis which plays a role in cancer metastasis nad seems to increase this quality of senescence cells likely because it’s being used in terms of energy metabolism so it’s making these senescence cells even more tumorigenic and while this study only looked at nicotinamide Montand nucleotides effect on cancer growth quite possible that nicotinamide right beside may show similar results in this very very specific context which is a type of cancer where pro-inflammatory senescence cells drive tumor growth that does not mean that nicotinamide mononucleotide or nicotinamide rye beside supplementation will cause cancer or even drive tumor progression and other types of cancer but I will say it would be nice to see long term animal studies to confirm I’m sure those are underway now let’s focus our attention on whether translation of all this preclinical data to humans is likely with the exception of the cancer study I just mentioned much of the preclinical data seems pretty promising but there are a couple of important points to make with respect to these animal studies that are very relevant for translating this data to humans first let’s talk about dose a majority of the Rhoden studies which to use nicotinamide right beside orally used a very high dose of nicotine mydrive aside in the range of 400 milligrams per kilogram body weight which translates to a human equivalent dose of 32 milligrams per kilogram body weight so for a hundred and eighty pound person that would be approximately two point six grams of nicotinamide right beside per day we will discuss human studies in a minute but that is a very high dose and it is a dose that is higher that has ever been lin eclis tested regarding the nicotinamide mononucleotide animal studies the majority of them all used very high dose about 500 milligrams per kilogram body weight and typically it was injected into the abdominal region of animals which makes it quite difficult to translate findings to humans the oral dose that was used in the long term aging study used a dose range on the low end the dose was a hundred milligrams per kilogram body weight which is a human equivalent dose of around 8 milligrams per kilogram body weight so for an hundred and eighty pound person that translates to about six hundred and fifty three milligrams of nicotine amide mononucleotide which seems pretty doable of course the mitigation of age associated physiological decline was much more robust at the high dose of 300 milligrams per kilogram body weight which is a human equivalent dose of 24 milligrams per kilogram body weight or approximately 2 grams of nicotinamide mononucleotide per day for a hundred and eighty pound person again that’s a pretty high dose the next point of concern is the bioavailability of either nicotinamide rai beside or nicotinamide mononucleotide the important point to address is whether nicotinamide right beside or nicotinamide mononucleotide can reach other tissues intact and directly form nad without going through that nad recycling pathway that I mentioned earlier called the salvage pathway the salvage pathway would mean that nicotinamide Rui beside or nicotinamide mononucleotide were first metabolized into just nicotinamide before forming nad instead of directly forming nad this is an important point because nad produced from the salvage pathway is subject to feedback inhibition and therefore cannot raise nad levels in tissues above a certain level so let’s talk about some details an animal study using isotope tracers allowed nad made directly from nicotinamide Rui beside or directly from nicotinamide mononucleotide vs nad made from nicotinamide via the salvage pathway to be measured what the study found was that at a low oral dose of around 50 milligrams per kilogram body weight of either nicotinamide ride beside or nicotinamide mononucleotide they produced very low levels of nad made directly from those precursors but only in the liver not in other tissues low levels of nicotinamide drive nad on the other hand were found in the kidneys and very low levels of nicotinamide drive nad were found in the muscles and also in the brain the human equivalent dose of 50 milligrams per kilogram body weight is roughly 4.
0 7 milligrams per kilogram body weight so for a hundred and eighty pound person that is approximately three hundred and thirty-two milligrams either nicotinamide right beside or nicotinamide mononucleotide which is a pretty doable dose but very little increases in nad were found at least in animals at that dose a higher oral dose was also done but only for nicotine my dry beside a dose of 200 milligrams per kilogram body weight of nicotinamide rai beside showed no difference compared to a low dose in terms of making nad direct from nicotinamide right aside in any other tissues other than the liver however more of the nad derived from the salvage pathway was found in the kidney muscle and the brain then at the lower dose so 200 milligrams per kilogram body weight translates to around a human equivalent dose of sixteen point three milligrams per kilogram body weight which for a hundred and eighty pound person is about 1.
3 grams which is pretty high when nicotinamide rai beside or nicotinamide mononucleotide were given intravenously at varying doses so fifty milligrams per kilogram body weight or 500 milligrams per kilogram body weight directly produced nad was found in the liver kidney and muscle in a dose-dependent manner however the only nad detected in the brain was that which was salvaged from nicotinamide suggesting that neither nicotinamide right beside nor nicotinamide mine a nucleotide across the blood-brain barrier it is noteworthy that had to head comparison of identical doses of injected nicotinamide rai beside and nicotinamide mononucleotide produced more nad made directly from nicotinamide right aside in the liver kidney and particularly in the muscle tissue compared to nicotinamide mononucleotide so what does this all mean and should we care what this data from the isotope tracer studies means is that even at very high oral doses neither nicotinamide rai beside or nicotinamide mononucleotide appeared to directly be transported to other tissues other than the liver at least again at those doses that were measured however nicotinamide rai beside and nicotinamide mononucleotide were converted into nicotinamide which then transported to other tissues and some of that nicotine mine was then converted into nad and at the end of the day isn’t raising cellular nad levels what is most important anyway the other animal studies a previously mentioned that showed positive health benefits and tissues like the muscle or the brain were at a very high oral dose of nicotinamide right aside and nicotinamide mononucleotide in fact in some cases they were double the dose so they were about 400 milligrams per kilogram body weight so it’s possible that nicotinamide right beside and nicotinamide mononucleotide can be transported to other tissues other than the liver at very very high oral doses but that’s yet to be shown however it’s also possible that at very very high doses the nad derived from the salvage pathway was high enough to do something beneficial the isotope data also suggests that if nicotinamide Rui beside or nicotinamide meinem nucleotide is administered intravenously both of those compounds are able to be transported to other tissues and directly form nad and not be subject to feedback inhibition this also raises nad levels in multiple tissues to a much higher concentration than otherwise would be of course IV injection of these nad boosters is very challenging to translate to humans you may be wondering why all the messing around with nad boosters like nicotinamide right beside and nicotinamide mononucleotide in the first place the reason nicotinamide Rui beside and nicotinamide mononucleotide are popular is because they can be transported into multiple tissue types including the liver kidney muscle and heart the brain is the exception neither nicotinamide right beside nor nicotinamide mononucleotide seem to be able to directly cross the blood-brain barrier but both form nicotinamide which can be transported into all tissue types including the brain where it can then form an ad so why not just go to the source and take or inject nad directly well for starters nad has poor bioavailability animal studies have shown that upon ingestion orally administered nad is primarily digested into the precursor nicotinamide but also to nicotine my drive aside and one nucleotide before being absorbed while oral bioavailability of NID is low the hope is that intravenous nad infusion may bypass that digestive system the problem is that no mammalian nad transporter has been identified and with the exception of the brain and the heart extracellular nad has not been shown to be taken up into tissues when nad was injected into the abdominal region of mice it was able to raise nad levels in some brain regions similarly mice that were injected with a high dose of nad had increased levels of nad in the heart and also protection from cardiac hypertrophy this suggest that direct injection of nad at a high dose may be doing something beneficial at least in the brain and in the heart I would like to mention that just because no data exists that does not mean that nad delivered intravenously cannot raise nad levels and other tissues other than the brain or the heart it’s possible that extracellular nad could be metabolized to nicotinamide and that could be transport to other tissues like muscle and also be converted into nad while there is very little preclinical data and zero clinical data on direct IV injection of nad it does seem like this may also be a good idea or a good area to explore as a potential way to boost energy levels and tissues but let’s move beyond what is plausible and talk about human data to date there is no published evidence of oral and nicotinamide mononucleotide supplementation in humans but there have been two randomized placebo-controlled trials showing that nicotinamide Ryba side can increase nad levels at least in white blood cells in a dose-dependent manner so let’s talk about those in an eight week long randomized double-blind placebo-controlled study involving a hundred and twenty healthy adults between the age of sixty and eighty years old a two hundred and fifty milligrams daily dose of nicotinamide right aside and pterostilbene a natural compound found in blueberries that activate sirtuin similar to resveratrol increased participants whole blood nad levels by 40 percent compared to their baseline levels just after four weeks participants whole blood nad levels increased by 90% when taking a double dose which was 500 milligrams those who took the lower dose exhibited reduced diastolic blood pressure and lower levels of the liver enzyme alanine aminotransferase which is a marker of liver damage however is difficult to know whether nicotinamide Ryba side pterostilbene or both are responsible for the effects on blood pressure and liver health previous clinical studies have found that pterostilbene reduced blood pressure at least in adults another randomized placebo-controlled trial involving 60 middle-aged and older adults between the ages of 55 and 79 years old demonstrated that a 500 milligram dose of nicotinamide right beside twice daily for a total of one gram per day for six weeks was well tolerated and increased nad levels in white blood cells by 60% the study participants also experienced improvements in blood pressure and aortic stiffness but these effects were not statistically significant possibly due to the size of the dose or the relatively small number of people in the study nicotinamide rai beside had no effects on metabolic function motor function or exercise capacity and performance that’s pretty much it for the randomized placebo controlled trials the data seems to indicate that oral and nicotinamide ride beside can raise nad levels in whole blood and in white blood cells but that’s the only conclusion that can be made the highest dose tested was one gram per day administered as 500 milligrams twice a day if we circle back to the animal data on nicotinamide right beside and all the benefits that were seen that was a human equivalent dose of 32 milligrams per kilogram body weight which is around 2.
6 grams per day for a hundred and eighty pound person while the short-term clinical studies show nicotinamide right beside given orally is safe at least in the short-term no long-term studies have been done it’s worth at least a small mention that nicotinamide right beside and nicotinamide mononucleotide both break down into nicotinamide over time especially in conditions of high humidity or high heat somewhat perplexingly supplemental nicotinamide may even reduce sirtuin activation the good news is that overall if these supplements are kept cold they are relatively stable and in MO such cases the supplements will contain very little nicotinamide so it’s a good idea to make sure that these products stay cool as much as possible and get them from a manufacturer to make sure that they have not been laying around in a hot warehouse somewhere longer than necessary okay just to recap nad is crucial for our survival it can be obtained from the diet but the body recycles it to get most of what it needs unfortunately day to day living and normal aging can cause nad levels to decline this causes metabolic and mitochondrial dysfunction as well as of a host of other problems associated with aging like increased DNA damage nad can be increased by things like exercise or fasting but also by nad boosters like nicotine my drive aside and nicotinamide mononucleotide however the data from nad boosters comes mostly from animal studies whether or not these nad boosters are effective and safe in humans in the long term is still an open question so those are my thoughts on the NAD rolled in a nutshell I think the data on the nad precursors is very promising and exciting however out of an abundance of caution much more still needs to be done before I’m ready to jump in with both feet I’m dr.
Rhonda Patrick and I’ll catch you next time